Cancer and rheumatoid arthritis (RA) share remarkably similar pathogenic pathways. For example, in both cancer and RA, angiogenesis, chronic inflammation and reactive oxygen species create a negative feedback loop that accelerates disease progression. In the synovium of RA patients, fibroblast-like synoviocytes (RA- FLS) has features of tumor-like transformation including anchorage-independent growth, adhesion to the extracellular matrix of cartilage, resistance to apoptotic signaling, and invasiveness to cartilage and bone. We have isolated a novel milk peptide mixture (AX-3) that inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and insulin receptor (IR). In vivo, AX-3 exhibits anti-cancer activity, increases the level of antioxidant enzyme Superoxide Dismutase, and reduces pro-inflammatory factors TNF-alpha, MCP-1, and RANTES. Recently, we further identified the active component of AX-3. These recent data and the understanding that inflammation, angiogenesis, hyperplasia, and oxidative stress are crucial mediators of RA led us to investigate the potential of AX-3 and its active component as therapeutic candidates for treating rheumatoid arthritis. In Specific Aim 1, AX-3 and its active component will be tested for their ability to induce apoptosis in RA-FLS. At lower dosages, the peptides will be assessed for inhibition of pro-inflammatory factor expressions in RA-FLS, and inhibition of several signaling pathways will also be tested. In Specific Aim 2, the in vivo effects of AX-3 and its active component on joint degradation and various biomarkers will be assessed using a collagen- induced RA rat model. In phase II study we will continue further molecular characterization and pharmacological studies based on the preliminary in vitro and animal results. The long term goal of this project is to develop a safe, effective, and cost-efficient therapy to treat RA.